Deficiency of intramuscular ICC increases fundic muscle excitability but does not impede nitrergic innervation

Abstract

The motility of the gastrointestinal tract is generated by smooth muscle cells and is controlled to a large extent by an intrinsic neural network. A gap of ∼200 nm usually separates nerve varicosities from smooth muscle cells, which suggests that direct innervation of the smooth muscle by synapses does not occur. Enteric nerves do make synapse-like contact with proposed regulatory cells, the interstitial cells of Cajal (ICC), which in turn may be in gap junction contact with smooth muscle cells. The role played by ICC in enteric innervation is controversial. Experimental evidence has been presented in vitro for the hypothesis that nitrergic inhibitory innervation is strongly reduced in the absence of ICC. However, in vivo data appear to dispute that. The present report provides evidence that explains the discrepancy between in vivo and in vitro data and provides evidence that inhibitory neurotransmitters can reach smooth muscle cells without hindrance when ICC are absent. The fundic musculature shows increased responses to substance P-mediated innervation and shows marked spontaneous activity, which is consistent with increased muscle excitability.

Interstitial cells of Cajal integrate excitatory and inhibitory neurotransmission with intestinal slow-wave activity

“…Whether the purinergic ATPdependent fIJP is regulated via ICC remains an outstanding question, which has to be addressed by conditional loss-offunction experiments in the future. Data from W/W v mice indicate that the purinergic fIJP potential is not altered by the loss of ICC subpopulations 41 .…”

Responses to Enteric Motor Neurons in the Gastric Fundus of Mice With Reduced Intramuscular Interstitial Cells of Cajal

“…Our findings suggest the possibility that reports of retained nitrergic responsiveness in Kit mutants may have included animals with only partial lesions in the ICC population. 14,15,17,25 Since the first experiments in which Kit mutants were used for functional studies of ICC, it was recognized that loss of ICC is incomplete in W/W V mice. 1 For example, ICC-MY are largely lost in the small intestine, but ICC-DMP (the equivalent of ICC-IM in the small bowel) are not reduced greatly in numbers.…”

“…[11][12][13] However, there is considerably more controversy regarding the role of ICC as mediators of enteric motor neurotransmission. Several publications have argued against the role of ICC as intermediaries in motor neurotransmission and suggested that changes in smooth muscle cells (SMCs) or other factors can account for differences in neural responses between wild-type animals and mutants in which ICC-IM are reduced (e.g., W/W V and Sl/Sl d mice and Ws/Ws rats [14][15][16][17] ). More recently, using a cell specific Cre-loxP approach, it was concluded that both ICC-IM and smooth muscle are involved in enteric nitrergic neural responses in the fundus.…”

The Significance of Interstitial Cells in Neurogastroenterology

“…Several studies have concluded that ICC-IM are not involved in nitrergic [222][223][224][225] or cholinergic neurotransmission. 222 229 These data support the hypothesis that ICC-IM mediate nitrergic inhibitory neurotransmission in the fundus and may explain the discrepancies in previous functional studies.…”